Clinical presentation,viral kinetics,and management of human monkeypox cases from New Delhi,India 2022

We describe the clinical and demographic characteristics, virological follow-up, and management of five confirmed monkeypox cases from New Delhi, India without any international travel history. The viral load kinetics and viral clearance were estimated in oropharyngeal swabs (OPS), nasopharyngeal swabs (NPS), EDTA blood, serum, urine, and various lesion specimens on every fourth day of follow-up ranging from 5 to 24 post onset day (POD) of illness. All five cases presented with mild to moderate-grade intermittent fever, myalgia, and lesions on the genitals, groins, lower limb, trunk, and upper limb. Four cases had non-tender firm lymphadenopathy. No secondary complications or sexually transmitted infections were recorded in these cases except for the presence of viral hepatitis B infection marker hepatitis B virus surface antigen (HBsAg) in one case. All the cases were mild and had a good recovery. A higher viral load was detected in lesion fluid (POD 9), followed by lesion roof (POD 9), urine (POD 5), lesion base (POD 5), and OPS/NPS (POD 5). The monkeypox virus (MPXV) DNA was detected in clinical samples from 5th to 24th POD. These monkeypox cases without international travel history suggest the underdiagnosed monkeypox infection in the community. This emphasizes the need for active surveillance of MPXV in the high-risk population such as men having sex with men and female sex workers.     

Impact of Age and Polytherapy on Fingolimod Induced Bradycardia: a Preclinical Study

Fingolimod is a an oral disease modifying drug for relapsing remitting multiple sclerosis (MS) preventing egress of B and T cells from lymph nodes. Relevant first dose adverse events include bradycardia and atrioventricular conduction slowing. Cardiac side effects of fingolimod and combinational pharmacotherapy including duloxetine and tolterodine were monitored in mice of different age using implantable ECG telemetric systems. Cardiac tissue was assessed for S1P-receptor subtype (1 and 3), and for GIRK1 expression. Fingolimod led to a significant heart rate reduction within 60 min, which returned to baseline values within 24 h. In older mice bradycardia was more pronounced compared to younger mice. Atrioventricular conduction was not affected. Older mice showed a higher S1PR3 expression in a naïve state and receptor expression was reduced after fingolimod administration. Combination with duloxetine or tolterodine alleviated fingolimod induced heart rate decrease. Our data provide preclinical evidence that negative chronotropic effects of fingolimod might be age dependent, possibly due to an altered expression and internalization of cardiac S1PR3 in older animals. This data could be relevant for future clinical monitoring and patient selection in the aging MS population. Combinational therapies of fingolimod and duloxetine or tolterodine are well tolerated and safe without an increased risk for pronounced bradycardia or arrhythmia.     

Biologics and immunomodulators for treating Crohn’s disease developing after surgery for an initial diagnosis of ulcerative colitis: a review of current literature

Crohn’s Disease (CD) or CD-like (CDL) conditions of the pouch are rare long-term inflammatory complications of patients who were initially diagnosed with ulcerative colitis (UC) who undergo total proctocolectomy with ileo-anal anastomosis (IPAA). There are no societal guidelines nor a consensus on their treatment, resulting in significant challenges for clinicians for their diagnosis and management. It is important to differentiate them from other more common pouch-related complications like pouchitis, cuffitis, irritable pouch syndrome, surgery associated stricture, and fistula. In this review, we focus on the less common presentation of CD and CDL conditions of the pouch and their treatment with the use of anti-TNF therapy with or without immunomodulator.     

Pathways of Translation: Deep Brain Stimulation

Electrical stimulation of the brain has a 2000 year history. Deep brain stimulation (DBS), one form of neurostimulation, is a functional neurosurgical approach in which a high‐frequency electrical current stimulates targeted brain structures for therapeutic benefit. It is an effective treatment for certain neuropathologic movement disorders and an emerging therapy for psychiatric conditions and epilepsy. Its translational journey did not follow the typical bench‐to‐bedside path, but rather reversed the process. The shift from ancient and medieval folkloric remedy to accepted medical practice began with independent discoveries about electricity during the 19th century and was fostered by technological advances of the 20th. In this paper, we review that journey and discuss how the quest to expand its applications and improve outcomes is taking DBS from the bedside back to the bench.     

A lowered salt intake does not compromise iodine status in Cape Town,South Africa,where salt iodization is mandatory

ObjectiveUniversal salt iodization is an effective strategy to optimize population-level iodine. At the same time as salt-lowering initiatives are encouraged globally, there is concern about compromised iodine intakes. This study investigated whether salt intakes at recommended levels resulted in a suboptimal iodine status in a country where salt is the vehicle for iodine fortification.MethodsThree 24-h urine samples were collected for the assessment of urinary sodium and one sample was taken for urinary iodine concentrations (UICs) in a convenience sample of 262 adult men and women in Cape Town, South Africa. Median UIC was compared across categories of sodium excretion equivalent to salt intakes lower than 5, 5 to 9, and greater than or equal to 9 g/d.ResultsThe median UIC was 120 μg/L (interquartile range 75.3–196.3), indicating iodine sufficiency. Less one-fourth (23.2%) of subjects had urinary sodium excretion values within the desirable range (salt <5 g/d), 50.7% had high values (5–9 g/d), and 22.8% had very high values (≥9 g/d). No association between urinary iodine and mean 3 × 24-h urinary sodium concentration was found (r = 0.087, P = 0.198) and UIC status did not differ according to urinary sodium categories (P = 0.804).ConclusionIn a country with mandatory universal salt iodization, consumers with salt intakes within the recommended range (<5 g/d) are iodine replete, and median UIC does not differ across categories of salt intake. This indicates that much of the dietary salt is provided from non-iodinated sources, presumably added to processed foods.     

HIV‐infected CD4+ T Cells Use T‐bet‐dependent Pathway for Production of IL‐10 Upon Antigen Recognition

Interleukin (IL)‐10 has been implicated in persistence of pathogens in a number of chronic infections. Infected CD4+ cells upon reactivation with HIV antigens were also shown to produce IL‐10, which might contribute to their persistence. Hence, it is crucial to determine mechanisms regulating IL‐10 production after activation with HIV antigens for devising effective blocking strategies. In this study, ERK‐, T‐bet‐ and FoxP3‐dependent pathways were evaluated for their possible roles in IL‐10 production by infected CD4+ cells after reactivation with HIV Env. Intracellular and secreted IL‐10 levels were determined by flow cytometry and Bioplex assay after treating PBMCs with PD98059, tipifarnib and cyclosporin A for blocking of ERK‐, T‐bet‐and FoxP3‐dependent pathways, respectively. Baseline levels of T‐bet, pERK were higher in P24+ CD4+ cells as compared to uninfected CD4+ cells, which increased further after activation with Env. Inhibition of T‐bet resulted in 2.3‐fold reduction of IL‐10 expression whereas ERK and FoxP3 inhibition failed to cause suppression of IL‐10 expression. Conversely, IL‐10 secreted by PBMCs was inhibited maximally after ERK inhibition suggesting its role in regulation of cytokine secretory pathway. IFN‐γ was found to be suppressed after treatment with inhibitors of all these pathways. Thus, the study highlighted need for IL‐10 blockade along with the use of antigens for therapeutic vaccinations or latency reversal and identified the T‐bet‐dependent pathway as an important pathway regulating IL‐10 production by infected CD4+ cells. However, simultaneous blockade of IFN‐γ precludes use of inhibitor of this pathway as an IL‐10 blocking strategy.